The mammalian endocannabinoid system (ECS) plays a role in nutrient intake, energy balance, immunity, inflammation and neurodegeneration, and many of these processes have been implicated in aging and age- related disease. However, a direct role for endocannabinoid signaling in the aging process has yet to be demonstrated. My discovery of an endocannabinoid system in the nematode C. elegans, combined with the observation that genetic manipulation of one of the endocannabinoid metabolizing enzymes extends lifespan, now suggests that this powerful model organism can be used to define the role of endocannabinoids in lifespan determination. Using gas chromatography-mass spectrometry (GC-MS) I have identified multiple endocannabinoid (EC) molecules in C. elegans, including isoforms of the mammalian endocannabinoid ligands. In worms endocannabinoids appear to have a role in reproductive development and formation of the dauer larva. As is the case in mammals, they also regulate feeding rates in both larvae and adults. EC levels increase with age in adult wild type animals but not in a long-lived insulin signaling mutant, suggesting that EC deficiency may associate with longevity. I have also found that chemical or genetic manipulation of the worm ortholog of fatty acid amide hydrolase (FAAH), the enzyme responsible for EC hydrolysis and inactivation, alters EC levels in a manner consistent with a conservation of function of this enzyme. Furthermore, transgenic over-expression of FAAH, which reduces endocannabinoid levels, leads to lifespan extension in adult animals and this longevity effect does not require the activity of the FOXO transcription factor DAF-16. These data provide the first evidence for the existence of a functional endocannabinoid system in the nematode and suggest that this powerful genetic model system can now be exploited to define which manipulations of the ECS are most beneficial in terms of healthspan, aging and age-related disease. In this proposal I will assess the effects of manipulating the endocannabinoid system on lifespan determination and measures of functional aging (healthspan). Since aging is a major risk factor for a number of diseases I will also examine the impact of these manipulations in established worm models of age-related disease. Finally I will undertake a targeted screen to identify the rate-limiting enzyme in endocannabinoid biosynthesis as this may provide a novel target for intervention. Together these studies will provide an opportunity to define the ways in which the endocannabinoid system can be manipulated to promote healthy aging as well as identifying novel therapeutic strategies for human aging and disease. PUBLIC HEALTH RELEVANCE: The mammalian endocannabinoid system plays a role in nutrient intake, energy balance, immunity, inflammation and neurodegeneration, and many of these processes have been implicated in aging and age- related disease. The discovery that genetic manipulation of a novel endocannabinoid system in the nematode C. elegans extends lifespan suggests that this invertebrate model system may be useful for defining a role of the endocannabinoid signaling in the aging process.